The Effect of a Combined Gluten- and Casein-Free Diet on Children and Adolescents with Autism Spectrum Disorders: A Systematic Review and Meta-Analysis

Abstract

There has been a growing interest in the gastrointestinal system and its significance for autism spectrum disorder (ASD), including the significance of adopting a gluten-free and casein-free (GFCF) diet. The objective was to investigate beneficial and safety of a GFCF diet among children with a diagnosis of ASD. We performed a systematic literature search in Medline, Embase, Cinahl, and the Cochrane Library up to January 2020 for existing systematic reviews and individual randomized controlled trials (RCTs). Studies were included if they investigated a GFCF diet compared to a regular diet in children aged 3 to 17 years diagnosed with ASD, with or without comorbidities. The quality of the identified existing reviews was assessed using A Measurement Tool to Assess Systematic Reviews (AMSTAR). The risk of bias in RCTs was assessed using the Cochrane Risk of Bias Tool, and overall quality of evidence was evaluated using Grades of Recommendation, Assessment, Development, and Evaluation (GRADE). We identified six relevant RCTs, which included 143 participants. The results from a random effect model showed no effect of a GFCF diet on clinician-reported autism core symptoms (standardized mean difference (SMD) −0.31 (95% Cl. −0.89, 0.27)), parent-reported functional level (mean difference (MD) 0.61 (95% Cl −5.92, 7.14)) or behavioral difficulties (MD 0.80 (95% Cl −6.56, 10.16)). On the contrary, a GFCF diet might trigger gastrointestinal adverse effects (relative risk (RR) 2.33 (95% Cl 0.69, 7.90)). The quality of evidence ranged from low to very low due to serious risk of bias, serious risk of inconsistency, and serious risk of imprecision. Clinical implications of the present findings may be careful consideration of introducing a GFCF diet to children with ASD. However, the limitations of the current literature hinder the possibility of drawing any solid conclusion, and more high-quality RCTs are needed. The protocol is registered at the Danish Health Authority website.

Cerebral Folate Deficiency, Folate Receptor Alpha Autoantibodies and Leucovorin (Folinic Acid) Treatment in Autism Spectrum Disorders: A Systematic Review and Meta-Analysis

“…This is believed to occur because milk contains the FRα protein which may react immunologically in the gut or cause an increase in cross-reactive FRAAs in the blood. Several types of diets (such as a casein-free diet) which have been reported to show some effectiveness in ASD are milk-free diets [98,99] although this has not been found in some studies [100]. Thus, it is possible that dietary treatments not uncommonly used to treat children with ASD may have a therapeutic effect by lowering the concentration of FRAAs in the blood.…”

The Gut-Microbiota-Brain Axis in Autism Spectrum Disorder

“…Diet plays a large role in determining gut microbial composition and function (23,24); thus, a selective diet could affect the gut microbial community. Some parents of children with ASD suspect that food allergies and sensitivity to dietary gluten and casein result in gastrointestinal problems and therefore implement gluten-free, casein-free (GF/CF) diets (25). However, despite the selective eating habits and specialized diets of some individuals on the autism spectrum, such as a GF/CF diet, there is no evidence of differential energy intake and growth compared to neurotypical children (26,27).…”

“…However, despite the selective eating habits and specialized diets of some individuals on the autism spectrum, such as a GF/CF diet, there is no evidence of differential energy intake and growth compared to neurotypical children (26,27). A small number of studies have found changes in ASD-related behaviors following implementation of a GF/CF diet (28), but many other studies have identified no such changes (25,29). Overall, the effect of a GF/CF diet on ASD behaviors remains inconclusive.…”

Is the gluten-free and casein-free diet efficacious in the treatment of childhood autism spectrum disorder?

“…Another systematic review based on the findings of six randomized controlled trials updated the evidence of the therapeutic effectiveness of the GFCF diet in childhood ASD and concluded that there is little evidence supporting beneficial effects of the diet (Piwowarczyk et al, 2018). A recent systematic review and meta-analysis, based on six relevant randomized controlled trials investigating possible benefits of the GFCF diet in children diagnosed with ASD found no effects on clinician-reported autism core symptoms, parent-reported functional level or behavioral difficulties (Keller et al, 2021). The quality of evidence ranged from low to very low due to serious risk of bias, inconsistency and imprecision.…”